B. Tom (Beril)http://repub.eur.nl/ppl/1473/
List of Publicationsenhttp://repub.eur.nl/eur_signature.pnghttp://repub.eur.nl/
RePub, Erasmus University RepositoryTherapeutic potential of SH2 domain-containing inositol-5′-phosphatase 1 (SHIP1) and SHIP2 inhibition in cancerhttp://repub.eur.nl/pub/38323/
Sun, 01 Jan 2012 00:00:01 GMT<div>G.M. Fuhler</div><div>R.H. Brook</div><div>B. Tom</div><div>S. Iyer</div><div>E.A. Gengo</div><div>M.Y. Park</div><div>M. Gumbleton</div><div>D.R. Viernes</div><div>J.D. Chisholm</div><div>W.G. Kerr</div>
Many tumors present with increased activation of the phosphatidylinositol 3-kinase (PI3K)-PtdIns(3,4,5)P3-protein kinase B (PKB/Akt) signaling pathway. It has long been thought that the lipid phosphatases SH2 domain-containing inositol-5′-phosphatase 1 (SHIP1) and SHIP2 act as tumor suppressors by counteracting with the survival signal induced by this pathway through hydrolysis or PtdIns(3,4,5)P3to PtdIns(3,4)P2. However, a growing body of evidence suggests that PtdInd(3,4)P2is capable of, and essential for, Akt activation, thus suggesting a potential role for SHIP1/2 enzymes as proto-oncogenes. We recently described a novel SHIP1-selective chemical inhibitor (3α-aminocholestane [3AC]) that is capable of killing malignant hematologic cells. In this study, we further investigate the biochemical consequences of 3AC treatment in multiple myeloma (MM) and demonstrate that SHIP1 inhibition arrests MM cell lines in either G0/G1 or G2/M stages of the cell cycle, leading to caspase activation and apoptosis. In addition, we show that in vivogrowth of MM cells is blocked by treatment of mice with the SHIP1 inhibitor 3AC. Furthermore, we identify three novel pan-SHIP1/2 inhibitors that efficiently kill MM cells through G2/M arrest, caspase activation and apoptosis induction. Interestingly, in SHIP2-expressing breast cancer cells that lack SHIP1 expression, pan-SHIP1/2 inhibition also reduces viable cell numbers, which can be rescued by addition of exogenous PtdIns(3,4)P2. In conclusion, this study shows that inhibition of SHIP1 and SHIP2 may have broad clinical application in the treatment of multiple tumor types.Angiotensin II type 2 receptor-mediated vasodilation. Focus on bradykinin, NO and endothelium-derived hyperpolarizing factor(s)http://repub.eur.nl/pub/69520/
Tue, 01 Feb 2005 00:00:01 GMT<div>W.W. Batenburg</div><div>B. Tom</div><div>M.P. Schuijt</div><div>A.H.J. Danser</div>
Angiotensin (Ang) II type 1 (AT1) receptors account for the majority of the cardiovascular effects Ang II, including vasoconstriction and growth stimulation. Recent evidence, mainly obtained in animals, suggests that Ang II type 2 (AT2) receptors counteract some or all of these effects. This review summarizes the current knowledge on the vasodilator effects induced by AT2 receptors in humans and animals, focussing not only on the mediators of this effect, but also on the modulatory role of age, gender, and endothelial function. It is concluded that AT2 receptor-mediated vasodilation most likely depends on the bradykinin-bradykinin type 2 (B 2) receptor-NO-cGMP pathway, although evidence for a direct link between AT2 and B2 receptors is currently lacking. If indeed B2 receptors are involved, this would imply that, in addition to NO, also the wide range of non-NO 'endothelium-derived hyperpolarizing factors' (EDHFs) that is released following B2 receptor activation (e.g., K+, cytochrome P450 products from arachidonic acid, H 2O2 and S-nitrososothiols), could contribute to AT 2 receptor-induced vasodilation.Selective angiotensin-converting enzyme C-domain inhibition is sufficient to prevent angiotensin I-induced vasoconstriction.http://repub.eur.nl/pub/13594/
Sat, 01 Jan 2005 00:00:01 GMT<div>J.H.M. Esch, van</div><div>B. Tom</div><div>V. Dive</div><div>W.W. Batenburg</div><div>D. Georgiadis</div><div>A. Yiotakis</div><div>J.M. van Gool</div><div>R.J. de Bruijn</div><div>R. de Vries</div><div>A.H.J. Danser</div>
Somatic angiotensin-converting enzyme (ACE) contains 2 domains (C-domain
and N-domain) capable of hydrolyzing angiotensin I (Ang I) and bradykinin.
Here we investigated the effect of the selective C-domain and N-domain
inhibitors RXPA380 and RXP407 on Ang I-induced vasoconstriction of porcine
femoral arteries (PFAs) and bradykinin-induced vasodilation of
preconstricted porcine coronary microarteries (PCMAs). Ang I
concentration-dependently constricted PFAs. RXPA380, at concentrations >1
mumol/L, shifted the Ang I concentration-response curve (CRC) 10-fold to
the right. This was comparable to the maximal shift observed with the ACE
inhibitors (ACEi) quinaprilat and captopril. RXP407 did not affect Ang I
at concentrations < or =0.1 mmol/L. Bradykinin concentration-dependently
relaxed PCMAs. RXPA380 (10 micromol/L) and RXP407 (0.1 mmol/L) potentiated
bradykinin, both inducing a leftward shift of the bradykinin CRC that
equaled approximately 50% of the maximal shift observed with quinaprilat.
Ang I added to blood plasma disappeared with a half life (t(1/2)) of
42+/-3 minutes. Quinaprilat increased the t(1/2) approximately 4-fold,
indicating that 71+/-6% of Ang I metabolism was attributable to ACE.
RXPA380 (10 micromol/L) and RXP407 (0.1 mmol/L) increased the t(1/2)
approximately 2-fold, thereby suggesting that both domains contribute to
conversion in plasma. In conclusion, tissue Ang I-II conversion depends
exclusively on the ACE C-domain, whereas both domains contribute to
conversion by soluble ACE and to bradykinin degradation at tissue sites.
Because tissue ACE (and not plasma ACE) determines the hypertensive
effects of Ang I, these data not only explain why N-domain inhibition does
not affect Ang I-induced vasoconstriction in vivo but also why ACEi exert
blood pressure-independent effects at low (C-domain-blocking) doses.New Aspects of Ace Inhibition: Importance of ACE co-localization with angiotensin and bradykinin receptorshttp://repub.eur.nl/pub/16169/
Wed, 03 Dec 2003 00:00:01 GMT<div>B. Tom</div>
The beneficial effect of angiotensin-converting enzyme (ACE) inhibitors in
hypertension and heart failure may relate, at least in part, to their capacity to interfere
with bradykinin metabolism. In addition, recent studies have provided evidence for
bradykinin-potentiating effects of ACE inhibitors that are independent of bradykinin
hydrolysis, i.e., ACE-bradykinin type 2 (B2) receptor ‘crosstalk’, resulting in B2
receptor upregulation and/or more efficient activation of signal transduction pathways,
as well as direct activation of bradykinin type 1 (B1) receptors by ACE inhibitors. This
review critically reviews the current evidence for hydrolysis-independent bradykinin
potentiation by ACE inhibitors, evaluating not only the many studies that have been
performed with ACE-resistant bradykinin analogues, but also paying attention to
angiotensin-(1-7) (Ang-(1-7)), a metabolite of both angiotensin (Ang) I and II, that
could act as an endogenous ACE inhibitor. The levels of Ang-(1-7) are increased
during ACE inhibition, and most studies suggest that its hypotensive effects are
mediated in a bradykinin-dependent manner.Superoxide does not mediate the acute vasoconstrictor effects of angiotensin II: A study in human and porcine arterieshttp://repub.eur.nl/pub/74038/
Mon, 01 Dec 2003 00:00:01 GMT<div>M.P. Schuijt</div><div>B. Tom</div><div>R. de Vries</div><div>P.R. Saxena</div><div>W.J. Sluiter</div><div>J.P. van Kats</div><div>A.H.J. Danser</div>
Objective: To investigate whether superoxide mediates angiotensin (Ang) II-induced vasoconstriction. Methods: Human coronary arteries (HCAs), porcine femoral arteries (PFA) and porcine coronary arteries (PCAs) were mounted in organ baths and concentration-response curves to Ang II, the nitric oxide (NO) donor S-nitroso-N-acetylpenicillamine (SNAP) and the NAD(P)H oxidase substrate NADH were constructed in the absence and presence of superoxide inhibiting and activating drugs. Extracellular superoxide was measured using cytochrome c reduction. Results: Ang II constricted both HCAs and PFAs. In HCAs, the NAD(P)H inhibitors diphenyleneiodonium (DPI) and apocynin, and the xanthine oxidase (XO) inhibitor allopurinol, but not the superoxide dismutase (SOD) mimetic tempol or the SOD inhibitor diethyldithiocarbamate (DETCA), reduced this constriction. Catalase potentiated Ang II in HCAs, indicating a vasodilator role for H 2O2. DPI, tempol and SOD did not affect Ang II in PFAs. DPI, apocynin and allopurinol relaxed preconstricted HCAs. Although the relaxant effects of the NO donor SNAP in PCAs was reduced by DETCA, indicating that superoxide-induced constrictions depend on NO inactivation, the apocynin-induced relaxations were NO independent. Moreover, NADH relaxed all vessels, and this effect was blocked by KCl but not DPI or NO removal. Xanthine plus XO also relaxed HCAs and PCAs. Incubation of human or porcine arteries with Ang II or NADH did not result in detectable increases of extracellular superoxide within 1 h. Conclusions: Acute vasoconstriction by Ang II is not mediated via superoxide generated through NAD(P)H oxidase and/or XO activation. Such activation, if occurring, rather results in the generation of the vasodilator H2O2.Bradykinin, angiotensin-(1-7), and ACE inhibitors: How do they interact?http://repub.eur.nl/pub/63564/
Sun, 01 Jun 2003 00:00:01 GMT<div>B. Tom</div><div>A. Dendorfer</div><div>A.H.J. Danser</div>
The beneficial effect of ACE inhibitors in hypertension and heart failure may relate, at least in part, to their capacity to interfere with bradykinin metabolism. In addition, recent studies have provided evidence for bradykinin-potentiating effects of ACE inhibitors that are independent of bradykinin hydrolysis, i.e. ACE-bradykinin type 2 (B2) receptor 'cross-talk', resulting in B2 receptor upregulation and/or more efficient activation of signal transduction pathways, as well as direct activation of bradykinin type 1 receptors by ACE inhibitors. This review critically reviews the current evidence for hydrolysis-independent bradykinin potentiation by ACE inhibitors, evaluating not only the many studies that have been performed with ACE-resistant bradykinin analogues, but also paying attention to angiotensin-(1-7), a metabolite of both angiotensin I and II, that could act as an endogenous ACE inhibitor. The levels of angiotensin-(1-7) are increased during ACE inhibition, and most studies suggest that its hypotensive effects are mediated in a bradykinin-dependent manner.ACE- versus chymase-dependent angiotensin II generation in human coronary arteries: A matter of efficiency?http://repub.eur.nl/pub/65413/
Sat, 01 Feb 2003 00:00:01 GMT<div>B. Tom</div><div>I.M. Garrelds</div><div>E. Scalbert</div><div>A.P.A. Stegmann</div><div>F. Boomsma</div><div>P.R. Saxena</div><div>A.H.J. Danser</div>
ACE-versus chymase-dependent angiotensin II generation in human coronary arteries: a matter of efficiency?http://repub.eur.nl/pub/10104/
Wed, 01 Jan 2003 00:00:01 GMT<div>B. Tom</div><div>I.M. Garrelds</div><div>E. Scalbert</div><div>A.P.A. Stegmann</div><div>F. Boomsma</div><div>P.R. Saxena</div><div>A.H.J. Danser</div>
OBJECTIVE: The objective of this study was to investigate ACE- and
chymase-dependent angiotensin I-to-II conversion in human coronary
arteries (HCAs). METHODS AND RESULTS: HCA rings were mounted in organ
baths, and concentration-response curves to angiotensin II, angiotensin I,
and the chymase-specific substrate Pro(11)-D-Ala(12)-angiotensin I
(PA-angiotensin I) were constructed. All angiotensins displayed similar
efficacy. For a given vasoconstriction, bath (but not interstitial)
angiotensin II during angiotensin I and PA-angiotensin I was lower than
during angiotensin II, indicating that interstitial (and not bath)
angiotensin II determines vasoconstriction. PA-angiotensin I increased
interstitial angiotensin II less efficiently than angiotensin I. Separate
inhibition of ACE (with captopril) and chymase (with C41 or chymostatin)
shifted the angiotensin I concentration-response curve approximately
5-fold to the right, whereas a 10-fold shift occurred during combined ACE
and chymase inhibition. Chymostatin, but not captopril and/or C41, reduced
bath angiotensin II and abolished PA-Ang I-induced vasoconstriction.
Perfused HCA segments, exposed luminally or adventitially to angiotensin
I, released angiotensin II into the luminal and adventitial fluid,
respectively, and this release was blocked by chymostatin. CONCLUSIONS:
Both ACE and chymase contribute to the generation of functionally active
angiotensin II in HCAs. However, because angiotensin II loss in the organ
bath is chymase-dependent, ACE-mediated conversion occurs more efficiently
(ie, closer to AT(1) receptors) than chymase-mediated conversion.Bradykinin potentiation by ACE inhibitors: A matter of metabolismhttp://repub.eur.nl/pub/61217/
Sun, 01 Sep 2002 00:00:01 GMT<div>B. Tom</div><div>A. Dendorfer</div><div>R. de Vries</div><div>P.R. Saxena</div><div>A.H.J. Danser</div>
Effects of donitriptan on carotid haemodynamics and cardiac output distribution in anaesthetized pigshttp://repub.eur.nl/pub/63255/
Mon, 24 Jun 2002 00:00:01 GMT<div>B. Tom</div><div>T.J. De Vries</div><div>J.P. Heiligers</div><div>E.W. Willems</div><div>K. Kapoor</div><div>G.W. John</div><div>P.R. Saxena</div>
The lack of vasoconstrictor effect of the pineal hormone melatonin in an animal model predictive of antimigraine activityhttp://repub.eur.nl/pub/72339/
Wed, 29 Aug 2001 00:00:01 GMT<div>B. Tom</div><div>T.J. De Vries</div><div>J.P. Heiligers</div><div>E.W. Willems</div><div>E. Scalbert</div><div>P. Delagrange</div><div>P.R. Saxena</div>
Negative inotropic effect of bradykinin in porcine isolated atrial trabeculae: Role of nitric oxidehttp://repub.eur.nl/pub/66251/
Wed, 11 Jul 2001 00:00:01 GMT<div>B. Tom</div><div>R. de Vries</div><div>P.R. Saxena</div><div>A.H.J. Danser</div>
Objectives: To investigate whether bradykinin affects cardiac contractility independently of its effects on coronary flow and noradrenaline release, and whether such inotropic effects, if present, are mediated via nitric oxide (NO). Methods: Right atrial trabeculae were obtained from 35 pigs, suspended in organ baths and attached to isometric transducers. Resting tension was set at approximately 750 mg and tissues were paced at 1.5 Hz. Tissue viability was checked by constructing a concentration response curve (CRC) to noradrenaline. Next, CRCs were constructed to bradykinin, either under baseline conditions or after pre-stimulation with the positive inotropic agent forskolin (1 or 10 μmol/l), in the absence or presence of the bradykinin type 2 (B2) receptor antagonist D-Arg [Hyp3-Thi5, d-Tic7, Oic8]-bradykinin (Hoe 140) (1 μmol/l), the NO synthase inhibitor Nω-nitro-L-arginine methyl ester (L-NAME) (100 μmol/l) and/or the NO scavenger hydroxocobalamin (200 μmol/l). Results: Bradykinin exerted a negative inotropic effect, both with and without forskolin pre-stimulation, reducing contractility by maximally 22 ± 3.6% (mean ± SEM) and 23 ± 3.6%, respectively (pEC50 8.37 ± 0.23 and 8.62 ± 0.22, respectively). L-NAME reduced this effect in pre-stimulated, but not in unstimulated, trabeculae. Hoe 140 and hydroxocobalamin fully blocked the inotropic effect of bradykinin. Conclusions: Bradykinin induces a modest negative inotropic effect in porcine atrial trabeculae that is mediated via B2 receptors and NO. The inconsistent results obtained with L-NAME suggest that it depends on NO synthesized de novo and/or NO from storage sites.α1-adrenoceptor subtypes mediating vasoconstriction in the carotid circulation of anaesthetized pigs: Possible avenues for antimigraine drug developmenthttp://repub.eur.nl/pub/63374/
Thu, 05 Jul 2001 00:00:01 GMT<div>E.W. Willems</div><div>J.P. Heiligers</div><div>T.J. De Vries</div><div>K. Kapoor</div><div>B. Tom</div><div>C.M. Villalón</div><div>P.R. Saxena</div>
A61603-induced vasoconstriction in porcine carotid vasculature: Involvement of a non-adrenergic mechanismhttp://repub.eur.nl/pub/72625/
Fri, 13 Apr 2001 00:00:01 GMT<div>E.W. Willems</div><div>J.P. Heiligers</div><div>T.J. De Vries</div><div>B. Tom</div><div>K. Kapoor</div><div>C.M. Villalón</div><div>P.R. Saxena</div>
It has recently been shown that the pharmacological profile of α1-adrenoceptors mediating constriction of porcine carotid arteriovenous anastomoses resembles that of α1A- and α1B-adrenoceptor subtypes. In an attempt to verify the involvement of α1A-adrenoceptors, we used the potent α1A-adrenoceptor agonist N-[5-(4,5-dihydro-1H-imidazol-2yl)-2-hydroxy-5,6,7,8-tetrahydro-naphthalen- 1-yl]methane sulphonamide (A61603) and found that intracarotid (i.c.) administration of A61603 (0.3-10 μg kg-1) dose-dependently decreased porcine carotid blood flow and vascular conductance. This decrease was exclusively due to a constriction of carotid arteriovenous anastomoses; the capillary blood flow and conductance remained unchanged. Surprisingly, the responses to A61603 were little modified by prior i.v. treatment with 5-methylurapidil (1000 μg kg-1), prazosin (100 μg kg-1) or a combination of prazosin and rauwolscine (100 and 300 μg kg-1, respectively). The 5-HT1B/1D receptor antagonist N-[4-methoxy-3-(4-methyl-1-piperazinyl) phenyl]-2′-methyl-4′(5-methyl-1,2,4-oxadiazol-3-yl)[1,1,- biphenyl]-4-carboxamide hydrochloride monohydrate (GR127935; 500 μg kg-1) and ketanserin (500 μg kg-1) also failed to modify carotid vascular responses to A61603, but, interestingly, methiothepin (3000 μg kg-1) proved to be an effective antagonist. Taken together, the present results show that A61603 is a relatively poor agonist at the α1A-adrenoceptor in anaesthetised pigs and that the carotid vasoconstriction produced by A61603 is mediated by a novel non-adrenergic mechanism.Bradykinin potentiation by angiotensin-(1-7) and ACE inhibitors correlates with ACE C- and N-domain blockadehttp://repub.eur.nl/pub/9693/
Mon, 01 Jan 2001 00:00:01 GMT<div>B. Tom</div><div>R. de Vries</div><div>P.R. Saxena</div><div>A.H.J. Danser</div>
ACE inhibitors block B(2) receptor desensitization, thereby potentiating
bradykinin beyond blocking its hydrolysis. Angiotensin (Ang)-(1-7) also
acts as an ACE inhibitor and, in addition, may stimulate bradykinin
release via angiotensin II type 2 receptors. In this study we compared the
bradykinin-potentiating effects of Ang-(1-7), quinaprilat, and captopril.
Porcine coronary arteries, obtained from 32 pigs, were mounted in organ
baths, preconstricted with prostaglandin F(2alpha), and exposed to
quinaprilat, captopril, Ang-(1-7), and/or bradykinin. Bradykinin induced
complete relaxation (pEC(50)=8.11+/-0.07, mean+/-SEM), whereas
quinaprilat, captopril, and Ang-(1-7) alone were without effect.
Quinaprilat shifted the bradykinin curve to the left in a biphasic manner:
a 5-fold shift at concentrations that specifically block the C-domain (0.1
to 1 nmol/L) and a 10-fold shift at concentrations that block both
domains. Captopril and Ang-(1-7) monophasically shifted the bradykinin
curve to the left, by a factor of 10 and 5, respectively. A 5-fold shift
was also observed when Ang-(1-7) was combined with 0.1 nmol/L quinaprilat.
Repeated exposure of porcine coronary arteries to 0.1 micromol/L
bradykinin induced B(2) receptor desensitization. The addition of 10
micromol/L quinaprilat or Ang-(1-7) to the bath, at a time when bradykinin
alone was no longer able to induce relaxation, fully restored the relaxant
effects of bradykinin. Angiotensin II type 1 or 2 receptor blockade did
not affect any of the observed effects of Ang-(1-7). In conclusion,
Ang-(1-7), like quinaprilat and captopril, potentiates bradykinin by
acting as an ACE inhibitor. Bradykinin potentiation is maximal when both
the ACE C- and N-terminal domains are inhibited. The inhibitory effects of
Ang-(1-7) are limited to the ACE C-domain, raising the possibility that
Ang-(1-7) synergistically increases the blood pressure-lowering effects of
N-domain-specific ACE inhibitors.L-NAME-resistant bradykinin-induced relaxation in porcine coronary arteries is NO-dependent: effect of ACE inhibition.http://repub.eur.nl/pub/12885/
Sat, 01 Jan 2000 00:00:01 GMT<div>A.H.J. Danser</div><div>B. Tom</div><div>R. de Vries</div><div>P.R. Saxena</div>
1. NO synthase (NOS)inhibitors partially block bradykinin (BK)-mediated
vasorelaxation. Here we investigated whether this is due to incomplete NOS
inhibition and/or NO release from storage sites. We also studied the
mechanism behind ACE inhibitor-mediated BK potentiation. 2. Porcine
coronary arteries (PCAs) were mounted in organ baths, preconstricted, and
exposed to BK or the ACE-resistant BK analogue Hyp(3)-Tyr(Me)(8)-BK
(HT-BK) with or without the NOS inhibitor L-NAME (100 microM), the NO
scavenger hydroxocobalamin (200 microM), the Ca(2+)-dependent K(+)-channel
blockers charybdotoxin+apamin (both 100 nM), or the ACE inhibitor
quinaprilat (10 microM). 3. BK and HT-BK dose-dependently relaxed
preconstricted vessels (pEC(50) 8.0+/-0.1 and 8.5+/-0.2, respectively).
pEC(50)'s were approximately 10 fold higher with quinaprilat, and
approximately 10 fold lower with L-NAME or charybdotoxin+apamin. Complete
blockade was obtained with hydroxocobalamin or L-NAME+
charybdotoxin+apamin. 4. Repeated exposure to 100 nM BK or HT-BK, to
deplete NO storage sites, produced progressively smaller vasorelaxant
responses. With L-NAME, the decrease in response occurred much more
rapidly. L-Arginine (10 mM) reversed the effect of L-NAME. 5. Adding
quinaprilat to the bath following repeated exposure (with or without
L-NAME), at the time BK and HT-BK no longer induced relaxation, fully
restored vasorelaxation, while quinaprilat alone had no effect.
Quinaprilat also relaxed vessels that, due to pretreatment with
hydroxocobalamin or L-NAME+charybdotoxin+apamin, previously had not
responded to BK. 6. In conclusion, L-NAME-resistant BK-induced relaxation
in PCAs depends on NO from storage sites, and is mediated via stimulation
of guanylyl cyclase and/or Ca(2+)-dependent K(+)-channels. ACE inhibitors
potentiate BK independent of their effect on BK metabolism.Positive inotropy of calcitonin gene-related peptide and amylin on porcine isolated myocardiumhttp://repub.eur.nl/pub/73085/
Fri, 03 Dec 1999 00:00:01 GMT<div>O. Saetrum Opgaard</div><div>R. de Vries</div><div>B. Tom</div><div>L. Edvinsson</div><div>P.R. Saxena</div>